Asthma is a non-infectious chronic inflammatory disease of the respiratory system characterized by a reversible airways obstruction. Acute airway obstruction, bronchial hyper-responsiveness and inflammatory state of the bronchial mucosa with increase levels of inflammatory mediators, are the most evident phenomenon which characterizes this pathology. Despite the increase in the prescribed anti-asthmatic treatments, the current trends indicate asthma is set to be the most chronic disease in industrialized countries, affecting mostly the children (15%) than the adults (10%).
In addition to asthma, another most common respiratory disorder is chronic obstructive pulmonary disease (COPD), which embraces several inflammatory pathologies that often co-exist. The WHO predicts COPD (Donnelly, L. E.; Rogers, D. F., Therapy for COPD in the 21st century, Drugs, 63, 1973-1998, 2003) will become the third most common cause of death world over by 2020 accounting 8.4 million lives. Although asthma for the last 25 years has been managed moderately with a combined bronchodilator and anti-inflammatory therapies, in contrast, COPD have no effective treatments currently, while the efficacy of the corticosteroids is controversial. Moreover chronic use of various anti-inflammatory drugs leads to adverse side effects. Hence, there is an urgent need to develop novel anti-inflammatory drugs having both the bronchodilatory and anti-inflammatory activity, having application to treat both COPD as well as asthma. Thus, the development of therapies for bronchial asthma has become the major focus of the pharmaceutical industry in the field of respiratory disorders.
Design and development of novel PDE-4 inhibitors (Yeoung, K,-P; Drug Discovery Today 14, 812-813, 2009; Houslay, M. D.; Schafer, P.; Zhang, K, Y, J. Drug Discovery Today 10, 1503-1519, 2005; Dal Piaz, V.; Giovannoni, M. P., Eur. J. Med. Chem., 35, 463-480, 2000; Giembycz, M. A. Monaldi Arch Chest Dis. 57, 48-64, 2002; Molfino, N. A., Respiration 72, 105-112, 2005; Conti, M.; Beavo, J. Annu. Rev. Biochem., 76, 481-511, 2007) in therapeutic applications have gained importance from the early 1990s. PDEs are a large family of enzymes that metabolise the second messenger cAMP/cGMP into inactive acyclic systems. The role of cAMP as a second messenger is well established and it modulates the response of immune cells to a variety of stimuli. Elevation of cAMP has generally been associated with inhibition of lymphocyte activity. The elevation of cAMP levels leads to the suppression of the synthesis and release of pro-inflammatory signals, cytokines and inhibit the production of reactive oxygen species.
The PD enzymes are a large family with eleven sub-families. Of these, the PDE-4, 7 and 8 are associated with the metabolism of cAMP. PDE-4 has four distinct genes, PDE-4A, PDE-4B, PDE-4C and PDE-4D (Muller, T.; Engels, P.; Fozard, J. R. Trends Pharmacol. Sci., 17, 294-298, 1996) with specificity to cAMP and thus have become potential therapeutic targets and most of the research is centred around PDE-4 inhibitors. The potential for selective PDE inhibitors to be used as therapeutic agents was predicted earlier (Teixeira, M. M.; Gristwood, R. W.; Cooper, N.; Hellewell, P. G. PDE-4 inhibitors: Trends Pharmacol. Sci., 18, 164-170, 1997). PDE-4 is the selective PD enzyme that metabolises the cAMP. Hence, PDE-4 inhibitors prevent the inactivation of cAMP.
Mesembrine, a major alkaloid present in Selectium torouosum, has been shown to act as a PDE-4 inhibitor (Smith, M.; Crouch, N.; Gericke, N.; Hirst, M. Psychoactive constituents of the genus Sceletium N.E.Br. and other Mesembryanthemaceae: review. J. Ethnopharmacol 50, 119-30, 1996; Pharmaceutical compositions containing mesembrine and related compounds. U.S. Pat. No. 6,288,104). This is the first catechol based natural product that showed PDE-4 activity. Theophylline is the oldest and shows a weak and non-specific PDE inhibition. The most popular and quite potential PDE-4 inhibitor, since its discovery, is rolipram (Griswold, D. E.; Webb, E. F.; Breton, J.; White, J. R.; Marshall, P. J.; Torphy, T. J., Effect of selective phosphodiesterase type IV inhibitor, rolipram, on fluid and cellular phases of inflammatory response, Inflammation 17, 333-44, 1993; Schneider, H. H.; Schmiechen, R.; Brezniski, M.; Seidler, J.; Eur. J. Pharmocol., 127, 105-115, 1986), a catechol based compound and structurally related to mesembrine. Rolipram, thus has become a template for the synthesis of novel inhibitors, besides becoming a reference drug in evaluating other inhibitors. Ariflo (cilomilast, SB-207,499; Profita, M, Chiappara G, Mirabella, F Chimenti, G Di, L, Costanzo, G, Riccobono, L Bellia V, Bousquet J, and Vignola A. Effect of cilomilast (Ariflo) on TNF-, IL-8 and GM-CSF release by airway cells of patients with COPD. 58, 573-579, 2003. Ochiai, H.; Ohtani, T.; Ishida, A.; Kusumi, K.; Kato, M.; Kohno, H.; Kishikawa, K.; Obata, T.; Nakai, H.; Toda, M. Bioorg. Med. Chem. Lett., 14, 207-10, 2004), roflumilast (Hatzelmann, A.; Schudt, C. J. Pharmacol. Exp. Ther. 297, 267-290, 2001), CDP-840, HT-0712, filaminast are some of the rolipram related active PDE-4 molecules, while V-11294A which is in phase-II clinical trials represents a hybrid molecule of xanthine and rolipram. Cilomilast, roflumilast, BAY-19-8004 and arofylline are in phase-III clinical trials.
The most common and worrisome aspect in the development of potent PDE-4 inhibitors is their propensity for side effects such as nausea and vomiting. The mechanism by which the PDE-4 inhibitors induce side effects are uncertain. However, the family of PDE-4 enzymes exist in two different conformational states (Souness, J. E.; Rao, S. Cell Signal, 9, 227-236, 1997; Duplantier, A. J. et al., J. Med. Chem. 39, 120-125, 1996), distinguishable with their affinity towards rolipram: the conformation with low affinity for rolipram is LAR conformation (PDE-4L), while the one with high affinity is known as HAR conformation (PDE-4H). PDE-4L is associated with anti-inflammatory activity, while the PDE-4H conformation correlates with adverse effects such as emsesis. Thus, there is till an urgent need for the development of promising PDE-4 inhibitors (a) related to rolipram structure or (b) structurally different class of compounds.
Rolipram, with the perspective of medicinal chemistry is a simple catechol derivate, resembling the alkaloid mesembrine. It has two pharmacophores: (a) 3,4-dialkoxy phenyl ring and (b) pyrrolidine-2-one. Though rolipram has disadvantages of the side effects, it has worked as an excellent model for the potent molecules like cilomilast/roflumilast (Phase-III) and others.
In the present invention it was thus desirable to prepare New Chemical Entities (NCEs) to realize the desirable features as a potent PDE-4 inhibitor. In the development of novel molecules it is anticipated to overcome the problems such as emesis, gastric acid secretion associated with rolipram, besides, aiming to dissociate catalytic site inhibition and binding site affinity. Therefore in the present work, development of selective and novel PDE-4 inhibitors was based on: (a) simple chemistry, (b) PDE-4 selectivity and (c) in vtrolin vivo strong potency.
Indoles, bis-indoles and octahydro indoles are part structures of several biologically active compounds (Higuchi, K.; Kawasaki, T. Nat. Pro. Rep. 24, 843-868, 2007; O'Connor, S. E.; Maresh, J. Nat. Pro. Rep. 23, 532-547, 2006). Indole ring system is a very important component in many synthetic pharmaceuticals (Olgen, S.; Kaessler, K.; Nebioglu, D.; Joachim, J. Chem. Biol. Drug Des., 70, 547-551, 2007; Smart, B. P.; Oslund, R. S.; Walsh, L. A.; Gelb, M. N. J. Med. Chem., 49, 2858-2860, 2006), while the World Drug Index contains 74 indole derivatives as drug molecules. Octahydro indole is part structure of mesembrine, an alkaloid with PDE-4 inhibitory activity. Furthermore, the indole 3-acetic acid and its derivatives have found use as building blocks for the synthesis of pharmaceutically important molecules (Hopkins, C. R. et al., Bioorg. Med. Chem. Lett., 15, 2734-2737, 2005) while, AWD-12-281, (PDE-4 active compound with lower emetic effects), which is in phase-III clinical trials, is an indole-glyoxamide derivative (Kuss, H.; Hoefgen, N.; Johanssen, S.; Kronbach, T.; Rundfeldt, C. J. Pharmacol. Exp. Ther. 307, 373-385, 2003). Likewise, the 1,3,5-triazine skeleton is implicated in a variety of therapeutic activities and some triazine derivates have shown anti-asthmatic activity (Leroux, F.; van keulen, B. J.; Daliers, J.; Pommery, N.; Henichart, J. P. Bioorg. Med. Chem. Lett., 7, 509-516,1999).
Thus, the present invention deals with the synthesis of NCEs based on novel ‘triazine-aryl-bis-indole’ skeleton (See for bis-indole based natural products: Ravikanth, V.; Imelda, O.; Wagner-Döbler, I.; Laatsch, H. J. Nat. Pro. 66, 1520-1523, 2003).
The thus prepared NCEs of the present invention are envisaged to address the problems associated with the earlier PDE-4 inhibitors and will have better and improved therapeutic indices. The present invention thus reports the synthesis of novel class of new ‘triazine-aryl-bis-indoles’, hybrid structures of substituted triazine, indoles and catechol in this patent, wherein, the new class of novel compounds differ with rolipram structurally: (a) the pyrrolidine ring system is replaced with a bis-indolyl acetic acid moiety and (b) the cyclopentyl group is replaced with a substituted triazinyl unit.

These structurally novel NCEs are envisaged as potential PDE-4 inhibitors devoid of the side effects. The suggested modifications in delineating a hybrid structure of Formula I is not obvious and lot of effort has gone in the designing of such a skeleton as represented in Formula I. The synthesis of the novel ‘triazine-aryl-bis-indole’ derivatives is reported for the first time in this patent. Likewise, the biological activity of the above NCEs is reported for the first time in this invention. The rationale in the design of the present invention for the synthesis of ‘triazine-aryl-bis-indoles’ are: (a) octahydroindole, indole and indole acetic acid are part structures of several pharmaceutically important compounds, besides, some anti-asthma compounds, (b) the triazines are also implicated in anti-asthma activity and (c) the catechol derived earlier compounds have shown reasonable PDE-4 activity. Hence, the hybrid structure proposed in the present invention is envisaged to show potent PDE-4 activity, devoid of the problems associated with earlier rolipram analogues, since the cyclopentyl moiety is replaced with hitherto unusal 1,3,5-trisubstituted triazinyl moiety.
Disclosure involves in vitro data showing PDE 4 inhibition by compound 7, IICT-TA67 molecule (FIG. 1, Table 1) as shown in FIG. 2. Disclosure also involves the in vivo data demonstrating the inhibition of airway hypersensitivity as an indicator of asthma as shown in FIG. 5. It further demonstrates the pharmacokinetics and bioavailability of this molecule in vivo as shown in Table 2.